Analyte permeable membrane systems for oxidative and optical stability

ABSTRACT

A sensor that may be used to detect the presence, amount, and/or concentration of an analyte in a medium within an animal. The sensor may include a sensor housing, an indicator element embedded within and/or covering at least a portion of the sensor housing, and a membrane over the indicator element. The membrane may reduce indicator element deterioration by preventing immune cells, such as white blood cells, from contacting the indicator element, substantially prevent transmission of light of at least a specified wavelength or range of wavelengths through the membrane, and/or permit the analyte to pass through to the indicator element. The membrane may be an opaque diffusion membrane. The sensor may include a foil. The foil may block light and/or reduce indicator element deterioration. The membrane may reduce oxidation of the indicator element.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority to U.S.Provisional Application Ser. No. 61/746,790, filed on Dec. 28, 2012, andU.S. Provisional Application Ser. No. 61/847,881, filed on Jul. 18,2013, which are incorporated herein by reference in their entirety.

BACKGROUND

1. Field of Invention

The present invention relates generally to sensors for implantation orinsertion within a living animal and measurement of a concentration ofan analyte in a medium within the living animal. Specifically, thepresent invention relates to sensors having a membrane over an indicatorelement on the surface of the sensor body.

2. Discussion of the Background

A sensor may include an indicator element, such as, for example,indicator molecules embedded or polymerized in or onto a polymer graft(i.e., layer or matrix). For example, in an implantablefluorescence-based glucose sensor, fluorescent indicator molecules mayreversibly bind glucose and, when illuminated with excitation light(e.g., light having a wavelength of approximately 378 nm), emit anamount of light (e.g., light in the range of 400 to 500 nm) that dependson whether glucose is bound to the indicator molecule.

If a sensor is implanted in the body of a living animal, the animal'simmune system begins to attack the sensor. For instance, if a sensor isimplanted in a human, white blood cells attack the sensor as a foreignbody, and, in the initial immune system onslaught, neutrophils are theprimary white blood cells attacking the sensor. Macrophages and giantcells may further attack the sensor. The defense mechanism ofneutrophils and other white blood cells includes the release of highlyoxidative substances known as reactive oxygen species (ROS), such ashydrogen peroxide (H₂O₂), hydroxyl radical (OH.), hypochlorite (OCl⁻),peroxynitrite (OONO⁻), and superoxide (O₂ ⁻).

ROS, such as hydrogen peroxide, may degrade indicator molecules. Forinstance, in indicator molecules having a boronate group, hydrogenperoxide may degrade the indicator molecules by oxidizing the boronategroup, thus disabling the ability of the indicator molecule to bindglucose.

In addition, if the sensor is an optical sensor, light (e.g., excitationlight, fluorescent light emitted by the indicator molecules) from thesensor may pass through the indicator element or other transparentportions of the sensor. If the sensor has been implanted in animaltissue, the light may be reflected by the tissue or may cause the tissueto fluoresce and return light at a different wavelength. The reflectedand fluoresced light from the tissue may return through the indicatorelement or other transparent part of the sensor and may be received byone or more light detectors (e.g., photodiodes) of the sensor. Thisresults in noise in the signals received by the light detectors.

Moreover, if the animal (e.g., a human patient) is in a brightly litarea, then the light may pass through the patient's skin and be receivedby the light detectors of the sensor. This could also introduce noiseinto the signals received by the light detectors. Thus, erroneous sensorreadings may occur because light detectors in an implanted sensor mayreceive additional signals unrelated to the analyte concentration.

There is presently a need in the art for improvements in optical sensorisolation and reducing indicator element degradation.

SUMMARY

The present invention overcomes the disadvantages of prior systems byproviding, among other advantages, improved optical isolation and/orreduced indicator element degradation while still allowing an analyte ofinterest to reach the indicator element.

One aspect of the present invention provides a sensor that may be usedfor in vivo detection of the presence, amount, and/or concentration ofan analyte in a medium within a living animal. The sensor may include asensor housing, an indicator element embedded within and/or covering atleast a portion of the sensor housing, and a membrane over at least aportion of the indicator element. The indicator element may includeindicator molecules.

In some embodiments, the membrane may have pores configured tosubstantially prevent white blood cells from passing through themembrane but to permit the analyte to pass through the membrane. Themembrane may be opaque. In some embodiments, the membrane may catalyzedegradation of ROS, such as hydrogen peroxide, and reduce deteriorationof the indicator element. The membrane may comprise a hydrophilic orhydrophobic membrane material.

In some embodiments, the membrane is a porous, opaque diffusion membranecovering at least a portion of the housing and the graft, and themembrane may be configured to substantially prevent white blood cellsfrom passing through the membrane and permit an analyte of interest topass through the membrane to the indicator element and to substantiallyprevent transmission of light of at least a specified wavelength orrange of wavelengths through the membrane. The diffusion membrane maycomprise an opaque or light absorbing colorant.

Further variations encompassed within the systems and methods aredescribed in the detailed description of the invention below.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and form partof the specification, illustrate various, non-limiting embodiments ofthe present invention. In the drawings, like reference numbers indicateidentical or functionally similar elements.

FIG. 1 is a schematic view of a sensor system, which includes animplantable sensor and a sensor reader, embodying aspects of the presentinvention.

FIG. 2 illustrates a perspective view of a sensor embodying aspects ofthe present invention.

FIG. 3 illustrates an exploded view of a sensor embodying aspects of thepresent invention.

FIGS. 4 and 5 illustrate perspective views of sensor components withinthe sensor body/shell/capsule of a sensor embodying aspects of thepresent invention.

FIG. 6 illustrates a side view of a sensor embodying aspects of thepresent invention.

FIG. 7 illustrates a cross-sectional end view of a sensor embodyingaspects of the present invention.

FIG. 8 illustrates a cross-sectional side view of a sensor in operationin accordance with an embodiment of the present invention.

FIGS. 9 and 10 illustrate a side view of a sensor, without and with amembrane over the indicator element, respectively, in accordance with anembodiment of the present invention.

FIGS. 11 and 12 illustrate a cross-sectional view of a sensor inaccordance with an embodiment of the present invention.

FIG. 13 is a perspective view of an alternate embodiment of a sensorembodying aspects of the present invention and comprising an opaquediffusion membrane substantially, or totally, covering the housing of asensor.

FIG. 14 is a transverse cross-section of the sensor and opaque diffusionmembrane along the line XIV-XIV in FIG. 13.

FIG. 15 is an alternate embodiment of a sensor covered with an opaquediffusion membrane.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This description may use relative spatial and/or orientation terms indescribing the position and/or orientation of a component, apparatus,location, feature, or a portion thereof. Unless specifically stated, orotherwise dictated by the context of the description, such terms,including, without limitation, top, bottom, above, below, under, on topof, upper, lower, left of, right of, inside, outside, inner, outer,proximal, distal, in front of, behind, next to, adjacent, between,horizontal, vertical, diagonal, longitudinal, transverse, etc., are usedfor convenience in referring to such component, apparatus, location,feature, or a portion thereof in the drawings and are not intended to belimiting. All patents, applications, published applications, and otherpublications referred to herein are incorporated by reference in theirentirety.

FIG. 1 is a schematic view of a sensor system embodying aspects of thepresent invention. In one non-limiting embodiment, the system includes asensor 100 and an external transceiver 101. In the embodiment shown inFIG. 1, the sensor 100 is implanted in a living animal (e.g., a livinghuman). The sensor 100 may be implanted, for example, in a livinganimal's arm, wrist, leg, abdomen, or other region of the living animalsuitable for sensor implantation. For example, as shown in FIG. 1, inone non-limiting embodiment, the sensor 100 may be implanted between theskin 109 and subcutaneous tissues 111. In some embodiments, the sensor100 may be an optical sensor. In some embodiments, the sensor 100 may bea chemical or biochemical sensor.

A transceiver 101 may be an electronic device that communicates with thesensor 100 to power the sensor 100 and/or obtain analyte (e.g., glucose)readings from the sensor 100. In non-limiting embodiments, thetransceiver 101 may be a handheld reader, a wristwatch, waistband, or anarmband. In other non-limiting embodiments, the transceiver 101 may beheld on a user's body by adhesive (e.g., as part of a biocompatiblepatch). In one embodiment, positioning (i.e., hovering orswiping/waiving/passing) the transceiver 101 within range over thesensor implant site (i.e., within proximity of the sensor 100) willcause the transceiver 101 to automatically convey a measurement commandto the sensor 100 and receive a reading from the sensor 100.

In some embodiments, the transceiver 101 may include an antenna 103, aprocessor 105 and/or a user interface 107. In one non-limitingembodiment, the user interface 107 may include a liquid crystal display(LCD), but, in other embodiments, different types of displays may beused.

In some embodiments, the antenna 103 may include an inductive element,such as, for example, a coil. The antenna 103 may generate anelectromagnetic wave or electrodynamic field (e.g., by using a coil) toinduce a current in an inductive element (e.g., inductive element 114 ofFIGS. 3-8) of the sensor 100, which powers the sensor 100. The antenna103 may also convey data (e.g., commands) to the sensor 100. Forexample, in a non-limiting embodiment, the antenna 103 may convey databy modulating the electromagnetic wave used to power the sensor 100(e.g., by modulating the current flowing through a coil of the antenna103). The modulation in the electromagnetic wave generated by thetransceiver 101 may be detected/extracted by the sensor 100. Moreover,the antenna 103 may receive data (e.g., measurement information) fromthe sensor 100. For example, in a non-limiting embodiment, the antenna103 may receive data by detecting modulations in the electromagneticwave generated by the sensor 100, e.g., by detecting modulations in thecurrent flowing through the coil of the antenna 103.

The inductive element of the antenna 103 and the inductive element(e.g., inductive element 114 of FIGS. 3-8) of the sensor 100 may be inany configuration that permits adequate field strength to be achievedwhen the two inductive elements are brought within adequate physicalproximity.

In some embodiments, the processor 105 may calculate one or more analyteconcentrations based on the analyte readings received from the sensor100. In some embodiments, the processor 105 may also generate one ormore alerts and/or alarms based on the calculated analyte concentrations(e.g., if the calculated analyte concentration exceeds or falls belowone or more thresholds). The calculated analyte concentrations, alerts,and/or alarms may be displayed via the user interface 107.

In some embodiments, the transceiver 101 may communicate (e.g., using awireless communication standard, such as, for example, Bluetooth) with aremote device (e.g., a smartphone, personal data assistant, handhelddevice, or laptop computer). The remote device may receive calculatedanalyte concentrations, alerts, and/or alarms from the transceiver 101and display them. Display by the remote device may be in addition to, orin the alternative to, display by the user interface 107 of thetransceiver 101. For example, in some embodiments, as illustrated inFIG. 1, the transceiver 101 may include a user interface 107, but thisis not required. In some alternative embodiments, the transceiver 101may not have a user interface 107, and calculated analyteconcentrations, alerts, and/or alarms may instead be displayed by aremote device.

In some non-limiting embodiments, the transceiver 101 may have some orall of the structure described in U.S. patent application Ser. No.13/937,871, which is incorporated herein by reference in its entirety,with particular reference to FIGS. 1 and 9.

FIGS. 2-8 illustrate a non-limiting embodiment of a sensor 100 embodyingaspects of the present invention that may be used in the sensor systemillustrated in FIG. 1. In some embodiments, the sensor 100 may be anoptical sensor. In one non-limiting embodiment, sensor 100 includes asensor housing 102 (i.e., body, shell, or capsule). In exemplaryembodiments, sensor housing 102 may be formed from a suitable, opticallytransmissive polymeric material, such as, for example, acrylic polymers(e.g., polymethylmethacrylate (PMMA)).

In the embodiment illustrated in FIGS. 2-8, the sensor 100 includesindicator molecules 104 (see, e.g., FIGS. 7 and 8). Indicator molecules104 may be fluorescent indicator molecules or absorption indicatormolecules. In some non-limiting embodiments, the indicator molecules 104may be as described in U.S. Pat. No. 6,344,360 or U.S. patentapplication Ser. No. 13/937,871, which are incorporated herein byreference in their entireties. In some non-limiting embodiments, sensor100 may include an indicator element 106. In some non-limitingembodiments, the indicator element 106 may be a polymer graft (i.e.,matrix layer or gel) coated or embedded on at least a portion of theexterior surface of the sensor housing 102, with the indicator molecules104 distributed throughout the graft. The indicator element 106 may beembedded within the sensor housing 102 and/or cover the entire surfaceof sensor housing 102 or only one or more portions of the surface ofhousing 102. Similarly, the indicator molecules 104 may be distributedthroughout the entire indicator element 106 or only throughout one ormore portions of the indicator element 106.

In the illustrated embodiment, the sensor 100 includes a light source108, which may be, for example, a light emitting diode (LED) or otherlight source that emits light over a range of wavelengths that interactwith the indicator molecules 104.

In the illustrated embodiment, sensor 100 also includes one or morephotodetectors 110 (e.g., photodiodes, phototransistors, photoresistors,or other photosensitive elements) which, in the case of afluorescence-based sensor, is sensitive to fluorescent light emitted bythe indicator molecules 104 such that a signal is generated by thephotodetector 110 in response thereto that is indicative of the level offluorescence of the indicator molecules and, thus, the amount of analyteof interest (e.g., glucose).

As illustrated in FIG. 8, some embodiments of sensor 100 include one ormore optical filters 112, such as high pass or band pass filters, thatmay cover a photosensitive side of the one or more photodetectors 110.

As shown in FIG. 8, in some embodiments, sensor 100 may be whollyself-contained. In other words, the sensor may be constructed in such away that no electrical leads extend into or out of the sensor housing102 to supply power to the sensor (e.g., for driving the light source108) or to convey signals from the sensor 100. Instead, in oneembodiment, sensor 100 may be powered by an external power source (e.g.,external transceiver 101). For example, the external power source maygenerate a magnetic field to induce a current in an inductive element114 (e.g., a coil or other inductive element). Additionally, the sensor100 may use the inductive element 114 to communicate information to anexternal sensor reader (e.g., transceiver 101). In some embodiments, theexternal power source and data reader may be the same device (e.g.,transceiver 101). Although, in FIG. 8, antenna 103 of transceiver 101 isillustrated as a coil that wraps around the sensor 100, this is notrequired. In some alternative embodiments, the sensor may have adifferent configuration, such as, for example, those described in U.S.patent application Ser. No. 13/650,016, which is incorporated herein byreference in its entirety, with particular reference to FIGS. 2A-2C, orthose described in U.S. patent application Ser. No. 13/937,871, which isincorporated herein by reference in its entirety.

In some embodiments, sensor 100 may include a semiconductor substrate116 and circuitry may be fabricated in the semiconductor substrate 116.The circuitry may include analog and/or digital circuitry. In someembodiments, the circuitry may incorporate some or all of the structuredescribed in U.S. patent application Ser. No. 13/650,016, which isincorporated herein by reference in its entirety, with particularreference to FIG. 11D. Also, although in some preferred embodiments thecircuitry is fabricated in the semiconductor substrate 116, inalternative embodiments, a portion or all of the circuitry may bemounted or otherwise attached to the semiconductor substrate 116. Inother words, in alternative embodiments, a portion or all of thecircuitry may include discrete circuit elements, an integrated circuit(e.g., an application specific integrated circuit (ASIC)) and/or otherelectronic components discrete and may be secured to the semiconductorsubstrate 116, which may provide communication paths between the varioussecured components.

In some embodiments, the one or more photodetectors 110 may be mountedon the semiconductor substrate 116, but, in some preferred embodiments,the one or more photodetectors 110 may be fabricated in thesemiconductor substrate 116. In some embodiments, the light source 108may be mounted on the semiconductor substrate 116. For example, in anon-limiting embodiment, the light source 108 may be flip-chip mountedon the semiconductor substrate 116. However, in some embodiments, thelight source 108 may be fabricated in the semiconductor substrate 116.

In some embodiments, the sensor 100 may include one or more capacitors118. The one or more capacitors 118 may be, for example, one or moretuning capacitors and/or one or more regulation capacitors. Further, theone or more capacitors 118 may be in addition to one or more capacitorsfabricated in the semiconductor substrate 116.

In some embodiments, the sensor 100 may include a reflector 119 (i.e.,mirror). Reflector 119 may be attached to the semiconductor substrate116 at an end thereof (see, FIG. 3). In a non-limiting embodiment,reflector 119 may be attached to the semiconductor substrate 116 so thata face portion 121 of reflector 119 is generally perpendicular to a topside of the semiconductor substrate 116 (i.e., the side of semiconductorsubstrate 116 on or in which the light source 108 and one or morephotodetectors 110 are mounted or fabricated) and faces the light source108. The face 121 of the reflector 119 may reflect radiation emitted bylight source 108. In other words, the reflector 119 may block radiationemitted by light source 108 from reaching the axial end of the sensor100.

According to one aspect of the invention, an application for which thesensor 100 was developed (although by no means the only application forwhich it is suitable) is measuring various biological analytes in theliving body of an animal (including a human). For example, sensor 100may be used to measure glucose, oxygen toxins, pharmaceuticals or otherdrugs, hormones, and other metabolic analytes in, for example, the humanbody. The specific composition of the indicator element 106 and theindicator molecules 104 therein may vary depending on the particularanalyte the sensor is to be used to detect and/or where the sensor is tobe used to detect the analyte (i.e., in interstitial fluid). Preferably,however, indicator element 106 should facilitate exposure of theindicator molecules to the analyte. Also, it is preferred that theoptical characteristics of the indicator molecules (e.g., the level offluorescence of fluorescent indicator molecules) be a function of theconcentration of the specific analyte to which the indicator moleculesare exposed.

FIGS. 4 and 5 illustrate perspective views of the sensor 100. In FIGS. 4and 5, the sensor housing 102, filters 112, and the reflector 119, whichmay be included in some embodiments of the sensor 100, are notillustrated. As shown in the illustrated embodiment, the inductiveelement 114 may comprise a coil 220. In one embodiment, coil 220 may bea copper coil but other conductive materials, such as, for example,screen printed gold, may alternatively be used. In some embodiments, thecoil 220 is formed around a ferrite core 222. Although core 222 isferrite in some embodiments, in other embodiments, other core materialsmay alternatively be used. In some embodiments, coil 220 is not formedaround a core. Although coil 220 is illustrated as a cylindrical coil inFIGS. 4 and 5, in other embodiments, coil 220 may be a different type ofcoil, such as, for example, a flat coil.

In some embodiments, coil 220 is formed on ferrite core 222 by printingthe coil 220 around the ferrite core 222 such that the major axis of thecoil 220 (magnetically) is parallel to the longitudinal axis of theferrite core 222. A non-limiting example of a coil printed on a ferritecore is described in U.S. Pat. No. 7,800,078, which is incorporatedherein by reference in its entirety. In an alternative embodiment, coil220 may be a wire-wound coil. However, embodiments in which coil 220 isa printed coil as opposed to a wire-wound coil are preferred becauseeach wire-wound coil is slightly different in characteristics due tomanufacturing tolerances, and it may be necessary to individually tuneeach sensor that uses a wire-wound coil to properly match the frequencyof operation with the associated antenna. Printed coils, by contrast,may be manufactured using automated techniques that provide a highdegree of reproducibility and homogeneity in physical characteristics,as well as reliability, which is important for implant applications, andincreases cost-effectiveness in manufacturing.

In some embodiments, a dielectric layer may be printed on top of thecoil 220. The dielectric layer may be, in a non-limiting embodiment, aglass based insulator that is screen printed and fired onto the coil220. In an exemplary embodiment, the one or more capacitors 118 and thesemiconductor substrate 116 may be mounted on vias through thedielectric.

In the illustrated embodiment, the one or more photodetectors 110include a first photodetector 224 and a second photodetector 226. Firstand second photodetectors 224 and 226 may be mounted on or fabricated inthe semiconductor substrate 116.

FIGS. 6 and 7 illustrate side and cross-sectional views, respectively,of the sensor 100 according to one embodiment. As illustrated in FIGS. 6and 7, the light source 108 may be positioned to emit light that travelswithin the sensor housing 102 and reaches the indicator molecules 104 ofthe indicator element 106, and the photodetectors 110, which may belocated beneath filters 112, may be positioned to receive light from theindicator molecules 104 of the indicator element 106.

In operation, as shown in FIG. 8, the light source 108 (e.g., an LED)may emit excitation light 329 that travels within the sensor housing 102and reaches the indicator molecules 104 of the indicator element 106. Ina non-limiting embodiment, the excitation light 329 may cause theindicator molecules 104 distributed in indicator element 106 tofluoresce. As the indicator element 106 may be permeable to the analyte(e.g., glucose) in the medium (e.g., blood or interstitial fluid) intowhich the sensor 100 is implanted, the indicator molecules 104 in theindicator element 106 may interact with the analyte in the medium and,when irradiated by the excitation light 329, may emit indicatorfluorescent light 331 indicative of the presence and/or concentration ofthe analyte in the medium.

The photodetectors 224 and 226 are used to receive light (see FIG. 3).Each photodetector 224 and 226 may be covered by a filter 112 thatallows only a certain subset of wavelengths of light to pass through(see FIG. 3). The filters 112 may be thin film (e.g., dichroic) filtersdeposited on glass, and the filters 112 may pass only a narrow band ofwavelengths and otherwise reflect the received light. The filters 112may be identical (e.g., both filters 112 may allow signal light to pass)or different (e.g., one filter 112 may allow signal light to pass, andthe other filter 112 may allow reference light to pass).

Photodetector 226 may be a reference photodetector, and the filter 112may pass light at the same wavelength as the wavelength of theexcitation light 329 emitted from the light source 108 (e.g., 378 nm).Photodetector 224 may be a signal photodetector that detects the amountof fluoresced light 331 that is emitted from the indicator molecules 104in the indicator element 106. In some non-limiting embodiments, thesignal filter 112 (i.e., the filter 112 covering photodetector 224) maypass light in the range of about 400 nm to 500 nm. Higher analyte levelsmay correspond to a greater amount of fluorescence of the molecules 104in the indicator element 106, and therefore, a greater amount of photonsstriking the signal photodetector 224.

Embodiments of the present invention may include one or more of severalpossible solutions to the light-blocking and/or indicator elementdeterioration problems described above.

FIGS. 9 and 10 illustrate a sensor 100 having a membrane 808 inaccordance with an embodiment of the present invention. FIG. 9 shows thesensor 100 without the membrane 808, and FIG. 10 shows the sensor 100with the membrane 808. In some non-limiting embodiments, the sensor 100may have a sensor housing/shell 102 and an indicator element 106embedded within and/or covering at least a portion of the housing 102.The indicator element 106 may include indicator molecules 104.

In regard to indicator element deterioration, as explained above, whiteblood cells, including neutrophils, may attack an implanted sensor 100.The neutrophils release, inter alia, hydrogen peroxide, which maydegrade indicator molecules 104 (e.g., by oxidizing a boronate group ofan indicator molecule and disabling the ability of the indicatormolecule to bind glucose).

As illustrated in FIGS. 9 and 10, in some non-limiting embodiments, theindicator element 106 may a have thin layer (e.g., 10 nm) on the outsideof the indicator element 106. The thin layer may protect againstindicator molecule degradation. The thin layer may be platinum, and theplatinum may be sputtered onto the outside surface of the indicatorelement 106, which includes the indicator molecules 104. Platinumrapidly catalyzes the conversion of hydrogen peroxide into water andoxygen, which are harmless to the sensor. The rate of this reaction ismuch faster than the boronate oxidation; thus, the platinum providessome protection against oxidation by reactive oxygen species. Althoughplatinum is the catalyst of the conversion of hydrogen peroxide intowater and oxygen in some embodiments, in alternative embodiments, othercatalysts of this reaction, such as, for example, palladium or catalase,may be used for the thin layer instead of or in addition to platinum.

As illustrated in FIG. 10, the sensor 100 may have a membrane 808 overthe indicator element 106 (and over any thin layer/film on the outsideof the indicator element 106). The membrane 808 may be opaque and,therefore, perform a light-blocking function. In other words, the opaquenature of the membrane may serve the function of effectively blockingextraneous light. In some non-limiting embodiments, only the opaquemembrane 808 is used to block light, and, in these embodiments, thesensor 100 does not include an additional layer, such as the layer 810illustrated in FIG. 11, over the membrane 808. However, in otherembodiments, the sensor 100 may include both a membrane 808 that isopaque and an additional layer, such as layer 810 illustrated in FIG.11, over the membrane 808.

In some non-limiting embodiments, the opaque membrane 808 may bephysically attached over the indicator element 106 after boring anadditional, smaller well into the capsule/housing 102. In somenon-limiting embodiments, the membrane 808 may be made of a meshmaterial, such as, for example, as a woven, non-woven, sintered,precipitated, or electrospun nylon. However, this is not required, and,in some alternative embodiments, the membrane 808 may be made of anothermaterial, such as, for example, cellulose acetate,polytetrafluoroethylene, polyethylene teraphthlate, polypropylene,polyvinyl alcohol, polybutylene terephthalate, polyether ether ketone,polyanhydride, polyamide, polyvinylchloride, polyethersulfone,polyvinylidene difluoride, polycarbonate, or derivatives thereof.

In some embodiments, the membrane 808 may be porous. In other words, themembrane 808 may be structured so that it channels one or more analytes(e.g., glucose) to the indicator element 106. For example, in onenon-limiting embodiment, the membrane 808 has small pores (e.g., poreshaving a pore size of microns or less) that block the passage of whiteblood cells (e.g., neutrophils), which are between 6 and 12 microns indiameter, from reaching the underlying indicator element 106 to attackit. The small pores, however, would at the same time be large enough toallow the analyte to reach the indicator element 106. In this way, aporous membrane 808 having small pores would increase sensor longevitywhile not affecting the ability of the sensor 100 to measure theconcentration of an analyte. In some embodiments, polymers that controlor reduce the body's response to an implant (i.e., the foreign bodyresponse) such as polyethylene oxides (PEO), hydroxy acrylates (HEMA),or fluoropolymers could be coated onto any of the membranes 808 (e.g.,polytetrafluoroethylene (PTFE) coated onto polyethylene teraphthlate(PET) or PEO coated onto nylon).

In some embodiments, the opaque membrane 808 may be made from a materialthat does not react adversely to the body's defenses. In non-limitingembodiments, the material from which the opaque membrane 808 is made mayadditionally be both porous (e.g., to allow and analyte, such asglucose, to flow through it) and opaque (e.g., to prevent light fromtraveling through it). For example, in some embodiments, the membranematerial may be a hydrophilic material, such as, for example, nylon orcellulose acetate. In other embodiments, the membrane material may be ahydrophobic material, such as, for example, polyethylene terephthalateor polytetrafluoroethylene.

FIGS. 11 and 12 illustrate a cross-sectional view of a sensor 100 havinga membrane 808 in accordance with another embodiment of the presentinvention. As illustrated in FIGS. 11 and 12, the indicator element 106of sensor 100 may be covered by a membrane 808, and the sensor 100 mayadditionally include a thin layer 810, which may also block light. Forexample, in some embodiments, the layer 810 may prevent excitation light329 from the light source 108 from escaping the sensor housing/capsule102 and prevent undesirable light entering the sensor housing/capsule102. This undesirable light may be from outside the body and/or may bereflected or fluoresced excitation light being returned from bodytissue. Reduction of each type of undesirable light would improve sensoraccuracy. In one non-limiting embodiment, the layer 810 may be a mirror.In one non-limiting embodiment, an additional smaller well may be boredinto the capsule/housing 102, a membrane 108 may be physically attachedover the indicator element 106, and an additional blocking layer 810 maythen be attached.

In some embodiments, the membrane 808 may channel an analyte to theindicator element 106, while the layer 810 and/or membrane 808simultaneously block any errant light.

The membrane 808 may be porous such that it does not physically blockthe analyte (e.g., glucose) from reaching the indicator element 106.Furthermore, the membrane 808 may have channels small enough to blockwhite blood cells from reaching the indicator element 106, but largeenough to allow for the passage of red blood cells and glucosemolecules.

In some non-limiting embodiments, the layer 810 may be a material thatdoes not adversely react to the body's defenses. In one non-limitingembodiment, platinum may serve as both the material for the membrane 808and as the material for the layer 810 because platinum catalyzeshydrogen peroxide species and reduces the deterioration of the indicatorelement 106 that would otherwise occur, while also blocking extraneouslight from over stimulating the indicator element 106. With a platinummembrane 808 in place, hydrogen peroxide, which is produced by apatient's white blood cells through the disproportionation of superoxide(O₂ ⁻), would quickly be catalyzed to water and oxygen, which areharmless to the transceiver 101. Thus, a platinum membrane 808 mayincrease the lifetime of the sensor 100 in the body.

In some alternative embodiments, polymers, such as, for example, nylon,cellulose acetate, polytetrafluoroethylene (PTFE), polyethyleneteraphthlate (PET), polypropylene (PP), polyvinyl alcohol (PVA),polybutylene terephthalate (PBT), polyether ether ketone (PEEK),polyanhydride, polyamide, polyvinylchloride (PVC), polyethersulfone(PES), polyvinylidene difluoride (PVDF), or polycarbonate mayadditionally or alternatively be used as the membrane material.

Platinum may not, however, offer complete protection from the in vivooxidation in all cases.

An alternative solution to the light blocking and immune response issuesis an opaque diffusion membrane that is configured to both block lightfrom entering or exiting the sensor housing and prevent reactive oxygenspecies-generating cells from direct tissue contact with the indicatorelement. A sensor assembly embodying aspects of the invention of thisalternative solution is represented by reference number 300 in FIG. 13,which is a perspective view of the sensor assembly. Sensor assembly 300comprises an implantable sensor, such as sensor 100 described above,covered or substantially covered by an opaque diffusion membrane 320.

FIG. 14 is a transverse cross-section of the sensor assembly 300. Forsimplicity of the figure, the internal components of the sensor, such asthe light source, filters, antennae, etc., are not shown in FIG. 14. Thesensor assembly 300 may comprise a sensor housing 102 which, asdescribed above, may comprise a suitable, optically transmissive polymermaterial, such as PMMA. Further, as described above, the sensor mayinclude an indicator element 106 coated on or embedded in at least aportion of the exterior surface of the housing 102. The diffusionmembrane 320 is disposed over the sensor housing 102 and indicatorelement 106. It should be noted that the relative thicknesses of thevarious layers of the sensor assembly 300 shown in FIG. 14 are forclarity of illustration and should not be viewed as limiting.

Preferably, the diffusion membrane 320 is made of a material that doesnot react adversely to the body's defenses but can also be effectivelymanipulated to be both porous to allow an analyte (e.g., glucose) toflow through the membrane and opaque to substantially prevent lighttransmission through the membrane. Suitable materials include, forexample, nylon or cellulose acetate because such materials arehydrophilic and can therefore be expected to allow an analyte solution(e.g., a glucose solution) to pass through pores formed in the material.Ready passage of the analyte solution through the membrane pores willfacilitate analyte readings with less of a time lag. In addition, porousmembranes formed from hydrophobic materials, such as polypropylene,polyethylene terephthalate (“PET”), and polytetrafluoroethylene(“PTFE”), can be made hydrophilic by known surface treatments methods,such as oxygen plasma treatment or chemical treatments to generatehydrophilic surface moieties or by grafting of hydrophilic polymers ontothe surface of hydrophobic materials, and thus allow facile diffusion ofanalyte solutions.

One example of an opaque diffusion membrane embodying aspects of theinvention may comprise a porous PET tube loaded with an opaque colorant(e.g., TiO2, carbon black). The total amount of colorant added to thePET may be altered such that no measurable light transmission throughthe diffusion membrane can be detected at the wavelengths of interest.For example, the amount of colorant added to the diffusion membranematerial may be increased to a point at which no measurable light istransmitted through the PET (or other membrane material) layer.

Preferably, in one embodiment, the opaque diffusion membrane 320 extendsover the entire sensor housing 102 covering substantially any and alllight paths into or out of the sensor housing. Preferably, the membranewould include end covers with or without wrapped ends.

A goal is to match light-blocking ability of the membrane 320 with theporosity of the membrane material. Accordingly, the percent open area ofthe membrane material is preferably sufficiently small (e.g., 6-25%) toblock light, but still has sufficient porosity to allow diffusion. Inone exemplary embodiment, PET membrane material could be tracked,etched, or laser drilled to add pores. In some non-limiting embodiments,the pores added to the PET membrane material may have a size at the exitthat prevents leukocytes (white blood cells), which have a size ofapproximately 7-80 microns, from passing through the pores. For example,in one non-limiting embodiment, the pores may have a size ofapproximately 5-7 microns at the exit.

Another important characteristic of the diffusion membrane 320 is toprovide maximum distance between the white blood cells and the indicatorelement 106. Thus, in one embodiment of a diffusion membrane 320embodying aspects of the invention, the membrane 320 comprises a PETlayer having a thickness of approximately 25 to 50 microns to keepimmune cells (e.g., white blood cells) at a sufficient distance awayfrom the indicator element 106.

As shown in FIG. 15, another embodiment of a diffusion membraneembodying aspects of the invention is configured to maintain asufficient distance between white blood cells and the indicator element106 and employs a combination of materials comprising a relatively thick(e.g., 50-200 micron) porous, torturous path material 330 disposedeither beneath or on top of the porous PET (or other material) layer 320to provide an additional optically isolating layer and to furtherincrease the distance between the immune cell (e.g., white blood cells)and the indicator element 106. A suitable material for the torturouspath layer includes nylon. The torturous path material 330 provides alonger path through which ROS produced by the white blood cells wouldneed to travel before reaching analyte-sensing indicator element 106 andthereby increases the degree to which the ROS are diluted and/ordegraded. Accordingly, the tortuous path material 330 enhances the whiteblood cell-blocking capability of such a multi-layer diffusion membranecomprising layers 320 and 330.

In some embodiments, the sensor 100 may include a plurality ofmembranes. For example, in some non-limiting embodiments, the sensor 100may include one or more catalytic membranes, one or more porous immuneresponse blocking membranes, and/or one or more light blockingmembranes. In one non-limiting embodiment, the sensor 100 may include acatalytic membrane on top of the indicator element 106, a porous immuneresponse blocking membrane on top of the catalytic membrane, and a lightblocking membrane on top of the porous immune response blockingmembrane. In another non-limiting embodiment, the membranes may bearranged over the indicator element 106 in a different order. In yetanother non-limiting embodiment, one or more of the plurality ofmembranes may have one or more functions (e.g., a sensor 100 may includemembrane having catalytic membrane and a membrane that blocks both lightand immune response).

Embodiments of the present invention have been fully described abovewith reference to the drawing figures. Although the invention has beendescribed based upon these preferred embodiments, it would be apparentto those of skill in the art that certain modifications, variations, andalternative constructions could be made to the described embodimentswithin the spirit and scope of the invention. For example, in someembodiments, the sensor 100 is a subcutaneous electrooptical sensor, butthis is not required, and, in other embodiments, the sensor 100 may be atranscutaneous and/or electrochemical sensor. Also, circuitry of thesensor 100 and reader 101 may be implemented in hardware, software, or acombination of hardware and software. The software may be implemented ascomputer executable instructions that, when executed by a processor,cause the processor to perform one or more functions.

What is claimed is:
 1. A sensor for in vivo detection of the presence,amount, and/or concentration of an analyte in a medium within a livinganimal, the sensor comprising: a sensor housing; an indicator elementembedded within and/or covering at least a portion of the sensorhousing; and a porous, opaque diffusion membrane covering at least aportion of the sensor housing and a portion of the indicator element,wherein the diffusion membrane is configured to substantially preventwhite blood cells from passing through the diffusion membrane and permitan analyte of interest to pass through the diffusion membrane to theindicator element and to substantially prevent transmission of light ofat least a specified wavelength or range of wavelengths through thediffusion membrane; wherein the diffusion membrane comprises a layer ofhydrophilic material and a layer of torturous path material disposedover or under the layer of hydrophilic material, and the torturous pathmaterial is configured to provide a longer path through which reactiveoxygen species produced by white blood cells would need to travel beforereaching the indicator element.
 2. The sensor of claim 1, wherein theanalyte is glucose.
 3. The sensor of claim 1, further comprising alayer.
 4. The sensor of claim 3, wherein the layer comprises platinum.5. The sensor of claim 3, wherein the layer is between the indicatorelement and the membrane.
 6. The sensor of claim 5, wherein the layer isa thin layer sputtered on the outside of the indicator element.
 7. Thesensor of claim 1, wherein the indicator element is a polymer graftincluding indicator molecules.
 8. The sensor of claim 1, wherein thesensor housing includes a light source and a light detector.
 9. Thesensor of claim 1, wherein the living animal is a human.
 10. The sensorof claim 1, wherein the medium is interstitial fluid.
 11. The sensor ofclaim 1, wherein the indicator element comprises a fluorescent indicatorelement.
 12. The sensor of claim 1, wherein the sensor housing comprisesan optically transmissive polymer material.
 13. The sensor of claim 1,wherein the sensor housing is a shell.
 14. The sensor of claim 1,wherein the sensor housing is a capsule.
 15. The sensor of claim 1,wherein the diffusion membrane has pores configured to substantiallyprevent white blood cells from passing through the membrane but topermit glucose to pass through the membrane.
 16. The sensor of claim 15,wherein the diffusion membrane has a porosity of 3-60%.
 17. The sensorof claim 15, wherein pores formed through the diffusion membrane have asize of 0.45-6 microns.
 18. The sensor of claim 1, wherein thehydrophilic layer has a thickness of 10-200 microns.
 19. The sensor ofclaim 1, wherein the torturous path material comprises nylon.
 20. Thesensor of claim 1, wherein the torturous path layer has a thickness of50-200 microns.
 21. The sensor of claim 1, wherein the diffusionmembrane comprises a layer of material selected from the groupconsisting of nylon, cellulose acetate, polytetrafluoroethylene,polyethylene teraphthlate, polypropylene, polyvinyl alcohol,polybutylene terephthalate, polyether ether ketone, polyanhydride,polyamide, polyvinylchloride, polyethersulfone, polyethyleneterephthalate, polyvinylidene difluoride, polytetrafluoroethylene,nitrocellulose, acrylate, poly(methyl methacrylate), polyacrylate homo-or copolymers, polycarbonate, derivatives thereof, and combinationsthereof.
 22. The sensor of claim 1, wherein the diffusion membrane has athickness of 10-200 microns.
 23. The sensor of claim 1, wherein thediffusion membrane comprises an amount of opaque or light absorbingcolorant such that light transmission through the diffusion membrane isreduced.
 24. A sensor for in vivo detection of the presence, amount,and/or concentration of an analyte in a medium within a living animal,the sensor comprising: a sensor housing; an indicator element embeddedwithin and/or covering at least a portion of the sensor housing; and aporous, opaque diffusion membrane covering at least a portion of thesensor housing and a portion of the indicator element, wherein thediffusion membrane is configured to substantially prevent white bloodcells from passing through the diffusion membrane and permit an analyteof interest and red blood cells to pass through the diffusion membraneto the indicator element and to substantially prevent transmission oflight of at least a specified wavelength or range of wavelengths throughthe diffusion membrane, and the diffusion membrane comprises an opaqueor light absorbing colorant.
 25. The sensor of claim 24, wherein theopaque or light absorbing colorant comprises TiO2 or carbon black.